Mp65-18 Identification of Molecular Targets in Bladder Cancer Variants Using Single-Cell Analysis

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology III (MP65)1 May 2024MP65-18 IDENTIFICATION OF MOLECULAR TARGETS IN BLADDER CANCER VARIANTS USING SINGLE-CELL ANALYSIS Heiko Yang, Hanbing Song, Paul Allegakoen, Kevin Lu, Elizabeth Yip, Keliana Hui, Kevin Chang, Corynn Kasap, Janae Gayle, Bradley A. Stohr, Maxwell V. Meng, Arun Wiita, Chien-Kuang Cornelia Ding, Jonathan Chou, Sima Porten, and Franklin W. Huang Heiko YangHeiko Yang , Hanbing SongHanbing Song , Paul AllegakoenPaul Allegakoen , Kevin LuKevin Lu , Elizabeth YipElizabeth Yip , Keliana HuiKeliana Hui , Kevin ChangKevin Chang , Corynn KasapCorynn Kasap , Janae GayleJanae Gayle , Bradley A. StohrBradley A. Stohr , Maxwell V. MengMaxwell V. Meng , Arun WiitaArun Wiita , Chien-Kuang Cornelia DingChien-Kuang Cornelia Ding , Jonathan ChouJonathan Chou , Sima PortenSima Porten , and Franklin W. HuangFranklin W. Huang View All Author Informationhttps://doi.org/10.1097/01.JU.0001008756.24343.22.18AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Variant subtypes in bladder cancer, also known as histologic variants, are clinically aggressive tumors associated with poor prognosis. The rarity of these tumors has made molecular characterization elusive using bulk transcriptional profiling. The aim of this study was to use single cell RNA sequencing to identify molecular features associated with variant subtypes that could be potential targets for therapy. METHODS: Fresh tissue from bladder cancer patients undergoing surgery at our institution was sequenced using a bead-based single-cell RNA sequencing platform (Seq-Well) to generate an atlas of 9 tumors containing variants (micropapillary, nested, squamous differentiation, pleomorphic giant-cell like, plasmacytoid, small cell) and 3 tumors with pure urothelial carcinoma (UC) histology. Pathologic diagnoses were independently confirmed. Analysis was performed using the Seurat package in R Studio. Immunostaining validation was performed on a separately banked cohort. Bulk RNA sequencing data and clinical data were extracted and analyzed from The Cancer Genome Atlas (TCGA) database. Chimeric Antigen Receptor (CAR) T cells targeting TM4SF1 were generated by lentiviral transduction of primary human T cells and tested against publicly available bladder cancer cell lines. RESULTS: Variant tumors were enriched in TM4SF1, a surface molecule that we demonstrate to be susceptible to CAR T therapy in vitro. Variants also share a cell state characterized by highly specific expression of MUC16 (CA125), which is enriched in metastatic sites, harbors transcriptional hallmarks of epithelial-mesenchymal transition and luminal-basal plasticity, and is associated with poor survival and resistance to chemotherapy. Finally, we find evidence of transcriptional mimicry between variants and similar appearing non-urothelial cells (e.g. plasmacytoid:plasma cell), suggesting common pathways between distinct cell types that could be exploited. CONCLUSIONS: We have identified several targetable molecular features within variant bladder cancer subtypes. These findings set a critical starting point for future therapeutic investigation. Source of Funding: California Urology Foundation (HY) © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e1084 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Heiko Yang More articles by this author Hanbing Song More articles by this author Paul Allegakoen More articles by this author Kevin Lu More articles by this author Elizabeth Yip More articles by this author Keliana Hui More articles by this author Kevin Chang More articles by this author Corynn Kasap More articles by this author Janae Gayle More articles by this author Bradley A. Stohr More articles by this author Maxwell V. Meng More articles by this author Arun Wiita More articles by this author Chien-Kuang Cornelia Ding More articles by this author Jonathan Chou More articles by this author Sima Porten More articles by this author Franklin W. Huang More articles by this author Expand All Advertisement PDF downloadLoading ...